) Background: Epidemiologic and experimental studies suggest that oral contraceptives (OCP) and fenretinide, N-(4hydroxypheny1) retinamide (4-HPR), may reduce the risk of developing epithelial ovarian cancer, but mechanisms underlying the chemopreventive activity of these agents remain unknown. Studies in primates and with human ovarian explants suggest that 4-HPR and progestins can induce TGF beta in stromal cells and apoptosis in the ovarian surface epithelium (OSE). Either 4-HPR or a combination of progestin and TGF beta can induce apoptosis in immortalized OSE (IOSE). 4-HPR can induce apoptosis in isolated normal OSE and this is enhanced with TGF beta. 4-HPR induces apoptosis in different tumor cell lines by generating reactive oxygen species or by binding to retinoic acid receptors. TGF beta and retinoids induce apoptosis by downregulating anti-apoptotic proteins. Hypotheses and Specific Aims: Based on these data, we will test the hypothesis that a combination of OCP and 4-HPR will induce apoptosis in a greater fraction of OSE than either agent alone, related in part to the production of TGF beta by ovarian stromal cells. We propose that 4-HPR induces apoptosis by stimulating production of reactive oxygen species, where as OCP components downregulate anti-apoptosis by stimulating production of reactive oxygen species, where as OCP components downregulate anti-apoptotoic proteins. TGF beta can augment apoptosis produced by 4-HPR or by progestin. In this portion of the SPORE we will (1) explore mechanisms underlying the chemopreventive activity of OCP and 4-HPR in OSE from women at normal and increased risk of ovarian cancer, (2) seek novel bio-markers for the impact of TGF beta on apoptosis induced by progestin, and (3) conduct a series of clinical trials to test the impact of OCP and an optimal dose of 4-HPR, individually and in combination, on induction of TGF beta in the stroma and apoptosis in the OSE of women at normal and increased risk of ovarian cancer. Significance: These studies may provide a rationale for the combined use of two promising agents for preventing ovarian cancer and elucidate mechanisms of their action.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA083639-03
Application #
6503518
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2001-09-28
Project End
2002-08-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
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